The tumor microenvironment is a determining factor in the growth, progression, and pathophysiology of tumor cells. Included in this regulatory compartment are stromal connective tissue and immune cells, vascular networks, extracellular matrix (ECM), and matricellular proteins. Matricellular proteins regulate many aspects of cell-ECM interactions. As a founding member of this functional family, SPARC (secreted protein acidic and rich in cysteine; also termed osteonectin and BM-40) inhibits cell adhesion and proliferation in vitro by contextual mechanisms that include: i) disruption of focal adhesions, and ii) abrogation of growth factor-receptor interactions and signaling. A major function has been revealed from studies on SPARC-null mice: SPARC enhances the production and/or assembly of ECM in a number of different organs and tissues. Moreover, relative to wild-type (WT) counterparts, mice lacking SPARC exhibit reduced amounts of connective tissue, accelerated wound closure, reduced foreign body encapsulation, and enhanced ectopic tumor growth. Despite the engrossing phenotype and the confirmed role of this matricellular protein in cell behavior, a signaling receptor or cell-associated binding partner for SPARC that could account for one or more of these pathologies has not been identified. Macrophages (MFs) comprise part of the tumor stroma, and their recruitment requires adhesion, migration, and cell-surface recognition of ECM and growth factors. By phage display technology we have identified the association of SPARC with integrin-linked kinase (ILK), an integrin-binding protein in focal/fibrillar adhesions that regulates cell shape, cytoskeleton, survival, and migration. We postulate that: a) the deadhesive and ECM regulatory functions of SPARC result from the capacity of SPARC to activate ILK (Aim 1), and b) SPARC-null mice grow large subcutaneous (sc) tumors due to compromised ILK activation, which leads to a diminished ECM that does not favor MF recruitment (Aim 2). An interrelationship between SPARC and MFs would be novel and highly significant for our understanding of inflammatory/stromal cell contributions to cancer. [unreadable] [unreadable] [unreadable]